RESUMO
BACKGROUND: Past research illuminated pivotal roles of dopamine D3 receptors (D3Rs) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms underlying these actions remain unclear. METHODS: We employed Cre-LoxP techniques to selectively delete D3R from presynaptic dopamine neurons or postsynaptic dopamine D1R-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, RT-PCR, voltammetry, optogenetics, microdialysis, and behavioral assays (n≥8) to functionally characterize the roles of presynaptic versus postsynaptic D3Rs in cocaine and opioid actions. RESULTS: Our results revealed D3R expression in â¼20% of midbrain dopamine neurons and â¼70% of D1R-expressing neurons in the nucleus accumbens. While D2R was expressed in â¼80% dopamine neurons, we found no D2R and D3R colocalization among these cells. Selective deletion of D3Rs from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked NAc dopamine release. Conversely, D3R deletion from D1R-expressing neurons attenuated locomotor responses to D1-like and D2-like agonists. Strikingly, D3R deletion from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D3R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D3R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D1R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia. CONCLUSIONS: We dissected presynaptic versus postsynaptic D3R function in the mesolimbic dopamine system. D2R and D3R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. The mesolimbic D3Rs are critically involved in the actions of opioids but not cocaine.
